Funded in December, 2007: $285000 for 3 years

Collaborating researchers at the Joslin Diabetes Center will investigate the immunological characteristics of the chronic inflammation associated with human weight gain and obesity that may underlie insulin resistance and diabetes.

Obesity is accompanied by chronic, low-grade inflammation, which is thought to promote insulin resistance, type 2 diabetes and other features of the “metabolic syndrome,” such as heart disease and atherosclerosis. Fat tissue is a primary site for initiating this inflammation. Interestingly, fat tissue in different areas of the body such as under the skin or inside the belly (or abdomen) appears to behave differently. The inflammation in abdominal fat, inside the belly and surrounding the internal organs, has a greater association with insulin resistance compared with subcutaneous fat under the skin.

Research in animals by these and other investigators has identified two major types of immune cells in fat tissue—macrophages and T cells—that appear to play major roles in the chronic inflammation associated with obesity and diabetes. To test whether normal immune processes that ordinarily suppress inflammation are dysregulated in obesity, they will study adipose tissue from non-diabetic men and women who are scheduled for elective abdominal surgery. Tissue samples will be removed during surgery from 30 consenting participants, half of whom are obese and half lean.

The investigators will then quantify and characterize four types of immune cells in the adipose tissue that surrounds organs, and in the adipose tissue from under the skin. The four types of immune cells they will study are conventional immune macrophages; fat-laden macrophages (called “foam cells”); conventional immune T cells; and regulatory T cells. Then they will analyze potential pro-inflammatory and anti-inflammatory interactions amongst the two types of macrophages (conventional and foam cell), the two types of T cells (conventional and regulatory), and fat-storing cells in the participants’ tissue samples. They will also study these interactions in tissue culture.

The researchers anticipate that the obese (compared with the lean) participants will have increased levels of fat-laden macrophages and decreased levels of regulatory T cells, which in combination result in chronic inflammation, and that the chronic inflammation correlates with increased fat storage, and ultimately with insulin resistance and type 2 diabetes.

Significance: The findings may lead to clinical studies of anti-inflammatory treatments to prevent chronic inflammation in fat tissues, and potentially the onset of diabetes, in people who are obese.

Macrophage and T-reg Participation in the Adipose Tissue Inflammation of Obese Humans

Obesity is accompanied by chronic, low-grade inflammation, which is thought to promote insulin resistance, type-2 diabetes, and other features of the “metabolic syndrome.” Adipose tissue is a primary site for initiating this inflammation, alterations in visceral fat having a greater association with insulin resistance than those in subcutaneous fat. Our three laboratories, with expertise in three very different areas, have recently joined forces to investigate the immunological underpinnings of the chronic inflammatory state associated with weight gain and obesity in mammals, in particular humans. Here, we propose to analyze in human fat the functions of what our (and others’) preliminary data have revealed are two key cell-types in rodent adipose tissue inflammation: macrophages and T cells. We will study immune system cell-types in adipose tissue from visceral and subcutaneous depots of lean and obese humans, including thirty non-diabetic men and women, aged 21-65 yr, specifically including 15 lean (BMI<27 kg/m2) and 15 obese (BMI>40 kg/m2) individuals.

Diane Mathis, Ph.D.

Dr. Diane Mathis obtained a B.Sc. from Wake Forest University and a Ph.D. from the University of Rochester. She performed postdoctoral studies at the Laboratoire de Génétique Moléculaire des Eucaryotes in Strasbourg, France, and at Stanford University Medical Center. She returned to France at the end of 1983, establishing a laboratory at the Institut de Genetique et de Biologie Moleculaire et Cellulaire in Strasbourg, in conjunction with Dr. Christophe Benoist. The lab moved to the Joslin Diabetes Center at the end of 1999. Dr. Mathis is currently a Professor of Medicine at Brigham and Women’s Hospital and Harvard Medical School, and is an Associate Research Director and Head of the Section on Immunology and Immunogenetics at Joslin, where she holds the William T. Young Chair in Diabetes Research. She is Director of the JDRF Center on Immunological Tolerance in Type-1 Diabetes at HMS, a Principal Faculty Member at the Harvard Stem Cell Institute and an Associate Faculty Member of The Broad Institute. Dr. Mathis was elected to the US National Academy of Sciences in 2003 and to the German Academy in 2007.

The lab works in the fields of T cell differentiation and autoimmunity, with a special emphasis on exploiting the most advanced transgenic and gene-targeting technology to engineer new mouse models.

Dr. Steven Shoelson is an internationally recognized leader in diabetes research. He received a Ph.D. in chemistry and a medical degree from the University of Chicago. After completing internship and residency training at the Brigham and Women’s Hospital in Boston, he joined the faculty at the Joslin Diabetes Center, and has stayed at the Joslin throughout his professional career. Dr. Shoelson currently heads the Section on Cellular and Molecular Physiology, and is the Helen and Morton Adler Chair and an Associate Director of Research at the Joslin Diabetes Center. He is Professor of Medicine and an affiliated member in the Department of Biological Chemistry and Molecular Pharmacology at Harvard Medical School. He has received numerous awards and honors, including a Burroughs Wellcome Fund Scholar Award in Experimental Therapeutics, the Excellence in Diabetes Research Award of the Juvenile Diabetes Research Foundation, and a MERIT award from the NIH.

Dr. Shoelson’s research focuses on understanding the pathogenesis of insulin resistance and type 2 diabetes, with a special interest in the link between obesity and inflammation.

Dr. Allison Goldfine is recognized as a leader in clinical diabetes research. She received her medical degree from the University of Pennsylvania. After completing internship and residency training in Internal Medicine at the University of Massachusetts in Worcester, she joined the Joslin Diabetes Center for subspecialty training in Endocrinology and Diabetes, and has stayed at the Joslin as faculty throughout her professional career. Dr. Goldfine is currently Assistant Director of Clinical Research at the Joslin Diabetes Center. She is an Assistant Professor of Medicine at Harvard Medical School. She has received numerous awards and honors, including a career development award from the American Diabetes Association.

Dr. Goldfine’s research focuses on understanding the physiologic processes underlying insulin resistance and type 2 diabetes in people, with a special interest in new therapies to treat or prevent development of diabetes and its complications. In other research, Dr. Shoelson’s laboratory recently discovered and created three-dimensional structures of the gene and protein mutations that cause maturity-onset diabetes of the young (MODY), a form of type 2 diabetes that is appearing more frequently among young people—an alarming trend related to increased obesity among the young. The findings of Dr. Shoelson’s laboratory create the potential for improved treatments.

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